Persons with hemochromatosis constitute a plentiful and willing source of blood for transfusion. Recent changes in federal regulations have eased restrictions on the use of blood from hemochromatosis subjects for transfusion, however, no data exist to guide the performance of phlebotomy therapy in a blood donor center setting. We established and evaluated a program for treating persons with hemochromatosis in a donor center, and making their blood available for transfusion. Phlebotomy therapy was performed free of charge regardless of whether subjects met criteria for allogeneic donation. Hemoglobin of 12.5 g/dL was used as the threshold for performing phlebotomy and decreases in the MCV were used to guide the endpoints of therapy. One hundred thirty subjects were consecutively enrolled: 74% were homozygous for the C282Y mutation in the HFE gene, 76% met eligibility criteria for allogeneic donation, and 55% were previous blood donors. A median of 20 weekly or biweekly phlebotomies (range 7-99) were performed before the MCV reached the targeted endpoint of 3% below baseline, at which time the ferritin was less than 30 mcg/L and the transferrin saturation less than 30%. The median phlebotomy interval necessary to keep the MCV at this level during maintenance therapy was 10 weeks. No incident seroconversions for agents of transfusion-transmissible disease occurred during 1,402 donations. All subjects testing positive for viral agents gave a prior history of deferrable risk. As of September 2004, hemochromatosis donors were contributing 16% of the red cell units collected for allogeneic use in the NIH Clinical Center. Due to the steady contributions of NIH hemochromatosis donors, it was not necessary to postpone surgery or acquire blood from outside suppliers during periods of low inventory, at a time when regional blood supplies were at critically low levels in other hospitals. Our data demonstrate that hemochromatosis subjects can safely and significantly augment the allogeneic blood supply. Provision of phlebotomy therapy unrestricted by considerations of cost or suitability for donation can improve access to care and remove incentives for incomplete risk disclosure. On-going efforts in this study have focused on evaluation of hemochromatosis subjects as allogeneic blood donors, determination of best phlebotomy practice, critical examination of the role of double red cell donation by apheresis in the management of HH subjects, on optimizing the use of changes in red cell indices as a guide to the endpoints of phlebotomy therapy, on delineating the effect of phlebotomy therapy on arthritic symptoms, and on assessing changes in serum non-transferrin bound iron levels during therapy. More recent studies in this cohort have indicated that there is a higher than expected incidence of thyroid abnormalities in hemochromatosis subjects followed on this protocol, including 30% of female subjects with homozygosity for the C282Y HFE mutation, and with evidence of both central and peripheral thyroid dysfunction. Of note, peripheral thyroid disease is associated with anti-thyroid antibodies, indicating that an initial iron-mediated insult to thyroid tissue may result in exposure of thyroid antigens and subsequent antibody formation. Symptoms in affected patients have included fatigue, depression, and anemia during therapy.